Trends in Endocrinology & Metabolism
ReviewDiverse roles for the LDL receptor family
Section snippets
Lessons learned from the LDL receptor
The discovery in 1974 [1] of a cellular pathway for the binding, internalization and degradation of plasma LDL led to the identification of the LDL receptor [2]. This receptor plays a crucial role in the homeostasis of cholesterol by mediating the cellular uptake of apolipoprotein E (apoE)- and apolipoprotein B (apoB)-containing lipoprotein particles. Mutations in the gene encoding the LDL receptor lead to high plasma cholesterol levels and the development of atherosclerotic lesions at an early
Cargo functions of LDL receptor family members
Members of the LDL receptor superfamily display an impressive capacity to transport molecules into the cell. Much of our knowledge regarding the physiological role of these receptors in cargo transport has been derived from the generation of mice deficient in these receptors.
Cytoplasmic adaptor protein binding to LDL receptor family members
Cytoplasmic domains of members of the LDL receptor family interact with an array of intracellular proteins 45, 46 (Table 2). These intracellular proteins are generally classified as adaptor or scaffold proteins and most contain phosphotyrosine-binding domains (PTB) or postsynaptic density 95 (PSD-95)/Disc-large/ZO-1 (PDZ) domains. Many of the identified proteins [such as disabled protein 1 (Dab1), c-Jun N-terminal kinases interacting protein 1 (JIP-1), membrane-associated guanylate kinase 1
Signaling function of LDL receptor family members
Recent studies indicate that certain LDL receptor family members also participate in signaling pathways. This is accomplished by cooperation with additional cell surface molecules that associate directly or indirectly with LDL receptor family members and cytoplasmic adaptor molecules that associate with their cytoplasmic tail.
Conclusions
Cargo transport by members of the LDL receptor family appears to be intimately coupled to the regulation of cellular physiology. Not only is this manifested by regulating levels of certain proteases, lipoproteins and effector molecules, but also by mediating direct cell-signaling responses to ligand binding. Indeed, the growing number of important molecules reported to interact with the cytoplasmic domains of LDL receptor homologs confirms their involvement in several important physiological
Acknowledgements
DKS is supported by grants from the National Institutes of Health (NIH) (HL-50784, HL-65939 and HL-54710). WSA is supported by grant HL61873 from NIH. SLG is supported by grant HL60551 from the NIH and by the Susan G. Komen Breast Cancer Foundation.
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